Signal transduction initiated by multiple cytokines and growth factor receptors is mediated by dedicated non-receptor tyrosine kinases of the Janus kinase (JAK) family. The four members of this family (JAK 1-3 and Tyk2) are multi-domain proteins of about 130 kDa and are highly homologous with respect to their domain structure. The catalytic kinase domain located at the C-terminus is preceded by a pseudokinase domain, a Src homology 2 (SH2) domain and the N-terminal FERM (four-point-one, ezrin, radixin and moesin homology) domain. The latter serves to facilitate the interaction between the JAK protein and the cytokine receptor. According to the canonical signaling pathway ligand binding to their cognate receptor triggers engagement of JAK kinases which, in a series of phosphorylation events targeting the receptor, the JAK's themselves and one or several of the 6 representatives of the STAT (signal transducer and activator of transcription) family members relay the signal into the cells. Phosphorylated STATs dimerize and migrate to the nucleus where they become part of transcriptional regulatory complexes which lead to transcription of responsive genes. The canonical JAK-STAT signaling pathway is evolutionary conserved and is active in multiple cell types where it is utilized by a variety of hormones, growth factors and cytokines and their receptors. This key signaling pathway has been elucidated over the last 25 years and has been the subject of multiple excellent reviews. See Cytokine receptors and the involvement of JAK kinases (from Cox and Cools, Chemistry & Biology 18, Mar. 25, 2011).
Due to their key roles in multiple cytokine pathways, JAK inhibitors are believed to be of therapeutic value for diseases in which JAK-dependent signaling is pathologically augmented. Inhibition of the four JAK kinases may represent an attractive therapeutic strategy for treating diseases and/or disorders associated with dysregulation of the immune system. Systemic as well as organ-restricted inhibition of JAK signaling is considered to be of high therapeutic value.